CN1038749C - Dibenz [b,f] [1,4] oxazepin-11(10H)-ones for multidrug resistance reversing agents - Google Patents

Dibenz [b,f] [1,4] oxazepin-11(10H)-ones for multidrug resistance reversing agents Download PDF

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CN1038749C
CN1038749C CN92109400A CN92109400A CN1038749C CN 1038749 C CN1038749 C CN 1038749C CN 92109400 A CN92109400 A CN 92109400A CN 92109400 A CN92109400 A CN 92109400A CN 1038749 C CN1038749 C CN 1038749C
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ethyl
trifluoromethyl
diethylin
dibenzo
chloro
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CN1069731A (en
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I·蒙阔维克
L·王
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Bristol Myers Squibb Co
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    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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Abstract

This invention relates to a compound of formula I. Compounds of formula I are useful for the reversal of multidrug resistance of cancer drugs.

Description

The method of preparation dibenzo [b, f] [1,4] oxygen azatropylidene-11 (10H) ketone
The dibenzo that the present invention relates to replace (b, f) (1,4) oxygen azepine _ 11 (10H) ketone, they are useful to inverse cancer cell to the multiple drug resistance of various kinds of cell cytotoxic drug.Therefore The compounds of this invention can be used for multiple medicine is had the adjuvant chemotherapy of drug-fast tumour.
With cell toxicity medicament treatment human tumor is integral part in the modern clinical cancer treatment.The major obstacle that influences cancer chemotherapy is the resistance of tumour cell to antitumor drug.Drug resistance in human malignant tumor can be from multiple mechanism, and what have particularly important is cancer cells to the crossed resistance of varied group of the lipophilic drugs that has irrelevant 26S Proteasome Structure and Function, and this phenomenon is called multiple drug resistance (MDR).
Measure all MDR cells in early days in the research, the common trait that draws is for to reduce in intracellular accumulation with respect to sensitive cells stable state medicine.Found this phenotype increasing often afterwards with plasmalemma glycoprotein (the P-gp molecular weight is 170KDa).This proteinic connotation is to obtain confirming with the ability of granting drug resistance in sensitive cells by P-gp gene (MDR-1) transfection of having been cloned in MDR.Referring to:
Grace Bradley，Peter F.Juranka& Victor Ling-Mechanisms of multidrug resistance，Bioch.Biophys.Acta，948，pp87-128(1988)；Jane A.Endicott & Victor Ling-The biochemistry of P-glycoprotein-mediated multidrug resistance，Ann.Rev.Biochem，58，pp137-171(1989)；James M.Ford &William N.Hait-Pharmacology of drugs that altermultidrug resistance in cancer，PharmacologicalReviews，42，pp155-199(1990).
P-gp is made up of two symmetric parts, and each part has an ATP-binding domain territory.Evidence suggests that it plays the function that the energy with substrate specificity widely relies on pump.Also in some normal human tissue, as suprarenal gland, kidney, colon and placenta have been found high-caliber relatively P-gp.Yet its physiological action and natural substrate thereof are not understood yet.P-gp may be as toxin and the unusual biological discharge of detoxifcation mechanism with normal presence.Clinical example investigation has found that derive from the tumour in the tissue of too expressing MDR-1 information usually, the P-gp level is to have improved.In addition, be apparent that, between the P-gp of hematologic malignancies that is difficult to treat with some drugs and early stage soft tissue sarcoma expresses direct dependency is arranged, and they under normal circumstances do not express P-gp.Referring to: Mace Rothenberg ﹠amp; Victor Ling-
Multidrug Resistance：Molecular Biology and Clinical
Relevance，J.Nat.Cancer Inst.，81，pp907-910，
(1989)；Helen s.L.Chan，paul S.Thorner，George
Haddad and Victor Ling-Immunohistochemical Detection
of P-glycoprotein：Prognostic Correlation in Soft
Tissue Sarcoma of Childhood，J.Clin，Oncol.，8，pp
689-704 (1990). the potential clinical effect that P-gp is risen has effectively been supported in these inventions in inherent and MDR posteriority, and the MDR greatest limit make that some cancer therapy is invalid.
Design the certain methods strategy and obtained clinical property MDR.An approach likely is for utilizing chemical sensitising agent, and it can suppress the active outflow of resistant cell Chinese traditional medicine.Comprise calcium antagonist, calmodulin inhibitor and some drugs analogue thereof are interior, the MDR that numerous compound has demonstrated in various degree reverses ability, these preparation major parts are fat-soluble, and may play effect as the P-gp substrate, thereby Depressant logistics inefficacy should competitively.The literature review of the brilliance of showing for the medicament that changes multiple drug resistance in cancer is published recently.Referring to:
James M.Ford & William N.
Hair-Pharmacology of Drugs that Alter Multidrug
Resistance in Cancer，Pharmacoloaical Reviews，42，pp
155-199(1990)；David J.Stewart & Willian K.Evans-
Non-chemotherapeutic Agents that potentiate
Chemotherapy Efficacy，Cancer Treatment Reviews，16，
pp1-40(1989).
Up to the present, using the main limitation factor of some MDR reversal agents on one's body at cancer patient is the toxicity that they are produced when reaching effective concentration in treatment.Thereby the challenge that faces is to seek the ideal MDR reversal agents, and it should be a high-efficiency low-toxicity, and is that institute is receptible on the pharmacology when clinical application.
We have found one group of dibenzo (b, f) (1,4) oxygen azepine _-11 (10H)-ketone that replace (abbreviate as hereinafter oxygen azepine _) recently, and they have efficiently that MDR reverses ability.Can find in 164,579 (publication on September 17th, 1969) at English Patent U.K Patent No.1 with the compound of oxygen azepine _ structurally associated of the present invention, this invention delivered the oxygen azepine of tool formula II _ R wherein 8Be hydrogen or halogen, R 17Be hydrogen or C 1-6Alkyl, and R 9And R 10In one the expression free amine group, and another the expression hydrogen atom.Formula II oxygen azepine _ have pain relieving, analgesic and calm character according to reports.In addition, people such as Nagrajan are at IndjanJournal of Experimental Biology 12, pp217-224, (at p229) (1974), in delivered formula III oxygen azepine _.The formula III compound carries out molecule inner ring condensation by formula IV compound and makes in hot DMF.
Figure C9210940000111
Similarly method also is used to prepare above-mentioned formula II compound.
Oxygen azepine through identifying formula II and formula III _ all do not have MDR to reverse active.
The present invention relates to dibenzo (b, f) (1,4)-oxygen azepine _-11 (10H) ketone or acceptable salt of its medicine of formula I,
Figure C9210940000112
Wherein
P is 1 to 3;
R 1And R 2Represent hydrogen or carboxyl groups R respectively independently 6CO-,
R wherein 6Be C 1-6Alkyl, C 3-7Cycloalkyl, C 2-7Alkenyl,
Aryl or have the group of following general formula,
Figure C9210940000121
R 3Be hydrogen or chlorine;
R 4And R 5Represent C respectively independently 1-6Alkyl.
Formula I compound is being useful aspect the multiple drug resistance that reverses cancer therapy drug.Therefore on the other hand, the present invention relates to adopt the adjuvant chemotherapy medicine of formula I compound conduct to the tumour of multiple drug resistant.
The present invention relates to dibenzo (b, f) (1,4)-oxygen azepine _-11 (10H)-ketone or acceptable salt of its medicine of formula I
Figure C9210940000122
Wherein
P is 1-3;
R 1And R 2Represent hydrogen or carboxyl groups R respectively independently 6CO-, wherein
R 6Be C 1-6Alkyl, C 3-7Cycloalkyl, C 2-7Alkenyl, aryl
Or has a group of following general formula
Figure C9210940000131
R 3Be hydrogen or chlorine;
R 4And R 5Represent C respectively independently 1-6Alkyl.
Preferred formula I compound is 1 for P wherein ,-COR 6Be selected from those compounds of following group.
Figure C9210940000132
Wherein n is 1-4.
Can form formula I compound (R wherein 1And R 2Be hydrogen, and R 3Be chlorine) formula I ' compound (route A) can prepare via several different methods, shown in the route A is preferable methods.
In the step 1 of route A, phenolic group hydrogen on the formula V compound and positively charged ion M exchange student accepted way of doing sth VI compound.Cationic example comprises sodium, potassium, and TBuA, and the benzyl triethyl ammonium ammonium etc.This permutoid reaction available bases achieves the goal, as salt of wormwood, and potassium hydroxide, potassium hydride KH, sodium hydride, sodium hydroxide, yellow soda ash, or quaternary ammonium hydroxide are as tetrabutylammonium or hydroxide benzyl triethyl ammonium ammonium.This reaction is carried out in inert organic solvents usually, as acetone, and acetonitrile, methylene dichloride, dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE, methyl alcohol, 2-methyl cellosolve, ethanol, Virahol, or diglyme.
The step 2 of route A is that reactant formula VI phenates and formula VII compound (wherein Y is a halogen, preferred fluorine or chlorine) are reacted and finish.This addition reaction is in the presence of alkali, as salt of wormwood and in inert organic solvents, and as acetonitrile, DMF, N,N-DIMETHYLACETAMIDE, 2-methyl cellosolve, ethanol, Virahol, or carry out in the diglyme.Preferred solvent for just-propyl alcohol, 2-methyl cellosolve or DMF, preferable solvent are 2-methyl cellosolve.This is reflected under the intensification condition and carries out, and preferably carries out under the reflux temperature of solvent for use.
If necessary, can on the free 3-amino of formula I ' compound, carry out single acidylate or two acidylate, with the same described R of identical or different implication 6The CO-group replaces one or two hydrogen atom.The acidylate technology of free aromatic amine is very sophisticated in this area.For example, with regard to single acidylate, can be with formula I ' compound and equimolar R 6COOH acid coupling in the presence of dewatering agent, dewatering agent such as dicyclohexyl carbodiimide or 1-ethoxycarbonyl-2-oxyethyl group-1,2-dihydroquinoline (EEDQ).Described in other dewatering agent such as the Synthesis pp453-463 (1972) those also are suitable.In addition, can be with R 6The carboxyl of COOH is converted into the active derivative that responds that can adopt in the N-acidylate.Such carboxy derivatives of available is an acyl halide; Acylimidazole; Acid azide; Mixed acid anhydride; Active ester, for example ester that forms with Vinyl chloroformate or isobutyl chlorocarbonate etc.; Phenylcarbamate; N-hydroxyl imide is as the imide that forms with N-hydroxy-succinamide or N-hydroxyl phthalimide etc.; And the reactive derivative that constitutes with hydroxybenzotriazole (HBT) or 4-methyl tetrazole-5-thio-ketone etc.; Or similar activity carboxylic acid derivative.Forming formula I compound, wherein R 1And R 2During for identical carboxyl groups, should add the identical acylating agent of qdx at least.On the other hand, when the different acyl group of two of needs, preferably substep is with different acylating agent processing.
Forming formula 1 compound, wherein R 3During for hydrogen, the 2-cl radical of formula I ' compound can be by hydrogenolysis, and, if necessary, can be with the amino acidylate of free 3-, same as above.In addition, formula I ' compound at first carries out acidylate, carries out the hydrogenolysis of 2-cl radical subsequently.
Synthesizing of formula V compounds has description fully in many patent documentations and publication.More convenient method is in order to those methods of the initial feed for preparing this patent compound in U.S. patent 4,808,624.The method of other adoptable preparation formula V compound has been done summary in the full disclosure part of same United States Patent (USP).
Route A In another embodiment, the series of steps shown in the route B can be used for obtaining formula I " compound.In this route, the R in the formula IX compound 1And R 2Definition is the same.So, work as R 1And R 2When being hydrogen, step 1 can not be carried out.Yet, R at least preferably 1Or R 2R for the same definition 6The CO-acyl group.Be more preferably R 1And R 2One of be acyl group, another is a hydrogen.This acyl group can be used as protecting group, can remove through alkaline hydrolysis in the step of back.Single acidylate in step 1 or two acidylate can adopt with the similar approach described in formula I ' compound and achieve the goal.
Carboxyl among the Compound I X in step 2 with conventional carboxyl-protecting group R 11Protect.Among the present invention adoptable in order to the blocking-up or the protection carboxylic acid function conventional carboxyl-protecting group be this art skilled person known those; and; if necessary, described group is preferably and availablely remainder in the molecule is not produced the method for any destruction, the group that is removed.For example, with chemistry or enzymically hydrolyse; Under mild conditions, handle with chemical reducing agent; With methods such as uviolizing or catalytic hydrogenations.The example of the carboxyl-protecting group that these are easy to remove comprises following segment, as C 1-6Alkyl, diphenyl-methyl (benzyhydryl), 2-menaphthyl, the 4-picolyl, phenacyl, acetonyl, 2,2,2-three chloroethyls, silyl such as trimethyl silyl and tert-butyl dimetylsilyl, phenyl, nuclear substituted phenyl, as the 4-chloro-phenyl-, tolyl and tert-butyl phenyl, phenyl C 1-6Alkyl, nuclear substituted phenyl C 1-6Alkyl such as benzyl, 4-methoxy-benzyl, 4-nitrobenzyl (right-nitrobenzyl), 2-nitrobenzyl and trityl group, methoxymethyl, 2,2,2-trichloro-ethoxycarbonyl, benzyloxymethyl, C 1-6Alkane carbonyl oxygen base (alkanoyloxy) C 1-6Alkyl such as acetyl-o-methyl, propionyl oxygen methyl, C 2-6Alkenyl is as vinyl and allyl group.Other suitable known " protecting group in the organic synthesis " (John Wiley that do not comprise that superincumbent carboxyl-protecting group can be shown at Theodora W.Greene; Sons, 1981) find in the 5th chapter, incorporate the part of this paper into as disclosure at this.When using in the present invention, particularly advantageous carboxyl-protecting group is an allyl group.
In step 3, use and the similar approach described in the route A step 1, with positively charged ion M exchange free phenol hydrogen atom.Formed formula XI compound reacts with formula VII compound in step 4, obtains formula XII compound, and wherein group W is represented The condition that is adopted in the step 4 is with used similar in the route A step 2.
Step 5 is that conventional carboxyl-protecting group is removed, and works as R 11During for allyl group, available three (dibenzalacetones), two palladiums (O) and triphenylphosphine are removed.
Step 6 is amine H 2NCH 2(CH 2) pNR 4R 5Obtain formula XIV benzamide with the condensation of formula XIII benzoic acid derivative, and with after alkali promote to be reset accepted way of doing sth XV compound.There are many methods to form benzamide, for example, set forth some representational methods in U.S. patent 4,808, the 624 full disclosures part from primary amine and the represented benzoic acid derivative of formula XIII.Formula XIV benzamide does not separate out usually, but uses alkali such as salt of wormwood immediately, changes it into formula XV compound.
Under heating, be preferably under the reflux temperature of solvent for use, in step 7, obtain formula I " benzo (b; f) (1; 4) oxygen azepine list, preferred solvent be those solvents of the interior cyclization of disturbing molecule not, the example comprises acetonitrile; 2-methyl cellosolve; N,N-DIMETHYLACETAMIDE, methyl alcohol, Virahol; or diglyme, particularly preferred solvent is a 2-methyl cellosolve.
If necessary, " compound can carry out chlorination to formula I on the 2-position in step 8, this chlorination reaction can be carried out with the standard method of chlorination aromatic ring; as using sulfur oxychloride in methylene dichloride; in acetate, use N-chlorination succinimide with chlorine, or other suitable chlorination method.
Work as R 1And R 2During for hydrogen and acyl group, this acyl group can be removed by basic hydrolysis, obtains formula I " or I compound, wherein-NR 1R 2Be free amine group, in the time of if needed, can be with this free amine group R 6The CO-group carries out single acidylate or two acidylate, to obtain the more compound in the scope of the invention.
Route B
Figure C9210940000201
In the application's book, the numeral in symbol " C " lower right corner limits the number of the carbon atom that a certain special groups may contain.For example, C 1-6Alkyl means the alkyl that contains 1 to 6 carbon atom of straight or branched, and such alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl, n-hexyl, alkyl groups such as 3-methyl amyl; C 2-6The thiazolinyl that alkenyl means straight or branched as, vinyl, allyl group, 1-propenyl, pseudoallyl, 1-butylene base, crotyl, 3-butenyl, methacrylic, 1,1-dimethyl-allyl, 1-hexenyl, groups such as 2-hexenyl; C 3-7Cycloalkyl mean as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl propyl group, cyclobutylmethyl, cyclobutyl ethyl, groups such as cyclopentyl-methyl; Aryl means that unsubstituted phenyl or difference are independently by 1-3 halogen, C 1-6Alkyl, C 1-6Alkoxyl group or C 1-6The phenyl that alkylthio replaced, as the 4-aminomethyl phenyl, 2,3-Dimethoxyphenyl, 2-methyl-3-ethoxyl phenenyl, 4-tert.-butoxy phenyl, 4-methylthio group-3-fluorophenyl, 2,4 dichloro benzene base, groups such as 2-chloro-4-bromophenyl; C 1-6Alkoxyl group means the alkoxy grp of straight or branched, as methoxyl group, and oxyethyl group, positive propoxy, isopropoxy, n-butoxy, uncle-butoxy, n-pentyloxy, positive hexyloxy, 3-methyl pentyloxy, etc.; C 1-6Alkylthio means the alkylthio of straight or branched, as methylthio group, and ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, uncle's butylthio, positive penta sulfenyl, just own sulfenyl, groups such as 3-methylpent sulfenyl; Halogen means fluorine, chlorine, bromine or iodine.
Drawn structural formula can be represented the structure of The compounds of this invention in this paper.Yet some compound among the present invention may exist with other tautomeric form, and hydrogen atom is wherein transferred to the other parts in the molecule, and interatomic chemical bond is reset thereupon in the molecule.Be understood that these structural formulas have represented all tautomeric forms that may exist up to now.
Following specific examples is used for illustrating the synthetic of representative compounds among the present invention, but they are not considered to that scope of the present invention is had any restriction.The compound that the present invention includes for preparation, but the method change of being adopted and needn't specifying.And, in order to prepare same compound and the change method, also be easy the people who in this area, is skilled in technique with slightly different mode.
Unless otherwise specified, all temperature mean centigradetemperature (℃).Nucleus magnetic resonance (NMR) spectral property means with tetramethylsilane (TMS) makes interior mark, with the chemical shifts (δ) of 1,000,000/(ppm) expressions.In proton N MR spectroscopic data with regard to the relative area of different shift value record corresponding to molecule in hydrogen atom number on the specific function base.The character of displacement (with regard to multiplicity) is registered as wide unimodal (bs), wide doublet (bd), wide triplet (bt), wide quartet (bq), unimodal (s), multiplet (m), doublet (d), quartet (q), triplet (t), dual doublet (dd), dual triplet (dt) and dual quartet (dq).The NMR solvent for use is DMSO-d 6(full deuterium methyl-sulphoxide), D 2O (heavy water), COCl 3(deuteriochloroform) and other conventional deuterate solvent.Infrared (IR) spectrum is described and is only comprised the absorption wavenumber (cm with functional group evaluation value -1).
Celite is the diatomaceous registered trademark of Johns-Manuille Products Co., Ltd.
Dummy suffix notation used herein is widely used conventional abbreviation in the present technique field, and some of them are:
MS: mass spectrum
HRMS: high resolution mass spectrum
DMF: dimethyl formamide
Ac: ethanoyl
ADR: Zorubicin
ActD: dactinomycin
DMSO: methyl-sulphoxide
Ph: phenyl
Embodiment 13-amino-2-chloro-10-(2-(diethylin) ethyl)-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-11 (10H)-ketone (Ia)
Figure C9210940000231
Under nitrogen atmosphere, handle the suspension (1.76g, 44mmol washed with Skellysolve A) of 60% sodium hydride in mineral oil with the 80ml n-propyl alcohol.In this liquid, add 6.44g (20mmol) 4-amino-5-chloro-N-(2-(diethylin) ethyl)-2-(2-hydroxybenzoyl) amine hydrochlorate and 4.51g (20mmol) 4-chloro-3-nitro-trifluoromethyl toluene.Mixture concentrates under vacuum then in the reaction down 6 hours that refluxes.Residue is at NaHCO 3The aqueous solution reaches the methylene dichloride with 1: 1: 1, distributes between the mixture that ether and normal hexane are formed.Organic phase is used 1NNaOH and water washing successively, handles with 20ml 1NHCl then.Filter collection precipitated solid is used washing with acetone, gets the crude product of 1.65g 3-amino-2-chloro-10-(2-(diethylin) ethyl)-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-11 (10H)-ketone (Ia) dihydrochlorides, and it is a light yellow solid.Merge mother liquor, use NaHCO 3Aqueous solution neutralization, and use CH 2Cl 2Extract.Extract is dry and concentrated, and residue is done stratographic analysis on silica, to contain the CH of 2-8% methyl alcohol 2Cl 2Make elutriant, following three components: a) first component is 430mg 4-amino-5-chloro-N-(2-(diethylin) ethyl)-N-(2-nitro-4-(trifluoromethyl) phenoxy group) benzamide, and it is a yellow amorphous solid, m.p.＞60 ℃.
1H NMR(CDCl 3)δ8.0-8.3(m，3H)，7.7-7.9(m，4H)，7.02(s，1H)，6.11(s，1H)，4.26(m，2H)，2.2-2.8(m，6H)，0.80(m，6H)；
MS(m/e)663；
Ultimate analysis C 27H 24ClF 6N 5O 6:
Calculated value: C 48.84, H 3.64, and N 10.55
Experimental value: C 50.75, H 4.00, N 9.85.b) second component is 359mg 3-amino-2-chloro-10-(2-(diethylin) ethyl)-7-(trifluoromethyl)-dibenzo (b, f) (1,4) oxygen azepine _-11 (10H)-ketone (Ia), it is a free alkali.
1H NMR (CDCl 3) δ 7.72 (s, 1H), 7.63 (d, 1H), 7.42 (d, 1H), 4.42 (s, 1H), 6.52 (s, 1H), 4.45 (s, 2H), 4.09 (+2H), 2.77 (t, 3H), 2.52 (q, 4H), 6.96 (t, 6H); Ms (m/e) 428 is corresponding to M+H +
Handle sample with the anhydrous HCl that is dissolved in the methyl alcohol, product merges with previous 1.65g solid, with methyl alcohol-ether recrystallization, gets the light beige solid of 1.85g, m.p.＞130 ℃.
Ultimate analysis C 20H 21ClF 3N 3O 22 HCl:
Calculated value: C 47.97, H 4.63, and N 8.39
Experimental value: C 47.74, H 4.58, N 8.33.c) the 3rd component is 68mg 4-amino-5-chloro-N-(2-(diethylin) ethyl)-2-hydroxy-n-(2-nitro-4-(trifluoromethyl) phenyl) benzamide, it is a yellow solid, m.p.＞100 ℃.
1H NMR(CDCl 3)δ8.10(s，1H)，7.96(s，2H)，6.38(s，1H)，6.21(s，1H)，4.39(s，2H)，4.2-4.4(m，2H)，2.7-3.2(m，6H)，1.2(m，6H)； MS(m/e)474.
In another experiment, can press legal system and be equipped with 3-amino-2-chloro-10-(2-(diethylin) ethyl)-7-(trifluoromethyl)-dibenzo (b, f) (1,4) oxygen azepine _-11 (10H)-ketone dihydrochloride: with 4-amino-5-chloro-N-(2-(diethylin) ethyl)-2-hydroxybenzamide (13.182g, 4-butyl ammonium 25mmol), K 2CO 3(1.73g, 12.5mmol) and 4-chloro-3-nitro-trifluoromethyl toluene (5.63g, 25mmol) mixture of doing in the 100ml n-propyl alcohol solution refluxed 14 hours, concentrated under vacuum then.Residue is at Na 2CO 3Distribute between the aqueous solution and the ethyl acetate (300ml).Organic phase uses 3 * 200ml water, 0.5NNaOH solution (50ml) and water to wash successively, handles with Skellysolve A then, until there being dark-brown droplet-shaped thing to separate.The decantation supernatant liquor with the acid treatment of 30ml 2N salt, produces precipitation.Filter collection solid with the ethyl acetate washing, gets the dihydrochloride of 5.84g (46.6%) title compound after the drying.
In another experiment, with the 4-butyl ammonium (52.73g) of 4-amino-5-chloro-N-(2-(diethylin) ethyl)-2-hydroxybenzamide, 4-chloro-3-nitro-trifluoromethyl toluene (22.56g, 0.1mol) and K 2CO 3(6.92g, 50mmol) stirring of the mixture in the 300ml 2-methyl cellosolve and reflux are 17 hours.Mixture concentrates under vacuum, and residue distributes between water and ethyl acetate.Organic phase is used 2 * 50ml1N NaOH successively, and 2 * l00ml water washing is handled with 50ml 2NHCl then.Filter collection solid sediment is used CH 2Cl 2With the ethyl acetate washing, behind the air drying, get the dihydrochloride of 29.44g (58.9%) title compound.
Embodiment 2N-(2-chloro-10; 11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b; f) (1; 4) the oxygen azepine _-the 3-yl) ethanamide (Ib) and N-ethanoyl-N-(2-chloro-10; 11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b; f) (1,4) oxygen azepine _-the 3-yl) ethanamide (Ic)
Compound I a in the vlil of 10ml diacetyl oxide 12 minutes, is concentrated under vacuum then.Residue is done stratographic analysis on silica, with the CH that contains 1.5% methyl alcohol 2Cl 2Make elutriant, at first obtain 295mg Compound I c, it is a yellow amorphous solid.
1H NMR(CDCl 3)δ7.97(s，1H)，7.72(d，1H)，7.49(d，1H)，7.45(s，1H)，7.13(s，1H)，4.2(t，2H)，2.89(t，2H)；
MS (m/e) 511. gets the monoacylated product Ib of 820mg then, and it is a beige solid, mp143-4 ℃.
Ultimate analysis C 22H 23ClF 3N 3O 30.5H 2O0.5CH 3CO 2H:
Calculated value: C 54.31; H 5.06; N 8.27.
Experimental value: C 54.68; H 5.11; N 7.93.
1H NMR(CDCl 3)δ 8.43(s，1H)，7.82(s，1H)，7.74(s，1H)，7.63(d，1H)，7.52(s，1H)，7.44(d，1H)，4.18(t，2H)，2.87(t，3H)，2.63(q，4H)，2.26(s，3H)，2.02(s，2H)，1.02(t，6H)；
MS(m/e)469.
Embodiment 3N-(10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl)-dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) ethanamide (Id) In the mixture that the 8ml methanol solution is formed, add the Pd/C of 10mg 10% to compounds ib (270mg) and ammonium formiate (220mg).It was stirred 5 hours filtration catalizer.Vacuum concentrated filtrate, residue is at NaHCO 3The aqueous solution and CH 2Cl 2Between distribute.The organic layer drying, concentrating under reduced pressure gets the 190mg title compound, and it is a white solid, mp75-85 ℃.
1H NMR(CDCl 3)δ8.34(s，1H)，7.75(d，1H)，7.65(t，2H)，7.46(s，1H)，7.40(dd，1H)，7.10(dd，1H)，4.10(t，2H)， 2.76(t，2H)，2.49(q，4H)，2.14(s ，3H)，0.96(t，6H)；
MS(m/e)434；
HRMS analyzes C 22H 24F 3N 3O 3
Calculated value: 436.1848.
Experimental value: 436.1846.
Embodiment 4N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-3-yl-benzamide (Ie)
Figure C9210940000301
To Compound I a (250mg, 0.5mmol) and triethylamine (102mg is 1mmol) in the anhydrous CH of 2ml 2Cl 2In the solution that stir on the limit of solution composition, and the adding Benzoyl chloride (141mg, 1mmol).Mixture stirred 1 hour, then at Na 2CO 3The aqueous solution and CH 2Cl 2Between distribute.Concentrating under reduced pressure after the organic phase drying, residue carries out silica gel column chromatography, to contain the CH of 5-10% methyl alcohol 2Cl 2Make elutriant, get the title compound of 182mg (68.3%), it is a yellow solid, mp67-69 ℃.
1H NMR(CDCl 3)δ8.55(s，1H)，7.90(d，1H)，7.55(m，8H)，4.05(m，2H)，2.72(q，2H)，2.50(m，5H)，0.96(m，6H)；
HRMS
Calculated value: C 27H 25ClF 3N 3O 3532.1615
Experimental value: 532.1627
Embodiment 5N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) crotonamide (If)
Repeat to prepare the universal method of Compound I e, except the crotonyl chloride with equimolar amount replaces Benzoyl chloride.The productive rate of title compound is 61.3%, and it is a yellow solid, mp 106-107 ℃.
1H NMR(CDCl 3)δ8.50(s，1H)，7.87(d，1H)，7.55(m，2H)，7.00(m，2H)，5.82(dd，2H)，4.25(m，3H)，2.95(m，1H)，2.75(m，1H)，1.85(q，6H)，1.10(m，6H).
HRMS
Calculated value: C 24H 26N 3O 3F 3Cl 496.1615.
Experimental value: 496.1605.
Embodiment 6N-(2-chloro-10,11-dihydro-10 (2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) propionic acid amide (Ig)
Figure C9210940000321
Repeat to prepare the method for Compound I e, except the propionyl chloride with equimolar amount replaces Benzoyl chloride, the reaction times is 12 hours.The productive rate of title compound is 75.0%, and it is a yellow oil.
1H NMR(CDCl 3)δ8.42(s，1H)，7.78(s，1H)，7.75 (s，1H)，7.60(d，1H)，7.45(d，1H)，7.35(dd，1H)，4.10(t，2H)，2.80(t，2H)，2.45(m，6H)，1.25(t，3H)，0.95(t，6H).
Calculated value: C 23H 26ClF 3N 3O 3484.1615.
Experimental value: 484.1612.
Embodiment 7N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) cyclopropane carboxamide (Ih)
Figure C9210940000331
Repeat to prepare the method for Compound I e, except the cyclopropanecarbonyl chloride with equimolar amount replaces Benzoyl chloride, the reaction times is 12 hours.The productive rate of title compound is 80.7%, and it is a yellow solid, mp115-116 ℃.
1H NMR(CDCl 3)δ8.39(s，1H)，7.80(s，1H)，7.75(s，1H)，7.58(d，1H)，7.42(s，1H)，7.25(q，1H)，4.10(t，2H)，2.70(t，2H)，2.50(q，3H)，1.55(m，3H)，1.07(s，1H)，1.05(m，2H)，0.95(t，6H).
Calculated value: C 24H 26ClF 3N 3O 3496.1615.
Experimental value: 496.1605.
Embodiment 8N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl)-2-methyl isobutyramide (Ii)
Repeat to prepare the method for Compound I e, except the isobutyryl chloride with equimolar amount replaces Benzoyl chloride, the reaction times is 2 hours.The productive rate of title compound is 81.6%, and it is a yellow solid, mp73-75 ℃.
1H NMR(CDCl 3)δ8.42(s，1H)，7.77(s，1H)，7.57(m，3H)，7.35 (s，1H)，4.0(m，2H)，2.70(t，2H)，2.5(m，4H)，1.25(d，6H)，1.15(s，1H)，0.95(m，6H).
HRMS
Calculated value: C 24H 28ClF 3N 3N 3O 3498.1771.
Experimental value: 498.1761
Embodiment 9N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) tetramethylene methane amide (Ij)
Figure C9210940000351
Repeat to prepare the method for Compound I e, except the tetramethylene formyl chloride with equimolar amount replaces Benzoyl chloride, the reaction times is 2 hours.The productive rate of title compound is 54.3%, and it is a yellow oil.
1H NMR(CDCl 3)δ8.48(s，1H)，7.80(s，1H)，7.60(m，3H)，7.40(m，1H)，4.04(m，3H)，3.18(m，1H)，2.70(t，3H)，2.48(q，4H)，2.30(m，3H)，1.98(m，1H)，0.97(m，6H).
Calculated value: C 25H 28ClF 3N 3O 3510.1771.
Experimental value: 510.1760.
Embodiment 10N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) cyclohexane carboxamide (Ik)
Figure C9210940000361
Repeat to prepare the method for Compound I e, except replacing Benzoyl chloride with the hexanaphthene formyl chloride, the reaction times is 20 hours.The productive rate of title compound is 83%, and it is a yellow solid, mp137-138 ℃.
1H NMR (CDCl 3)δ8.50(s，1H)，7.87(s，1H)，7.86(s，1H)，7.68(d，1H)，7.55(s，1H)，7.47(d，1H)，4.15(t，2H)，2.82(t，2H)，2.56(q，4H)，2.35(m，1H)，1.2-2.1(m，10H)，1.00(t，6H).
Calculated value: C 27H 31ClF 3N 3O 3538.2084.
Experimental value: 538.2076.
Embodiment 11N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) the oxygen azepine _-the 3-yl)-N-(ring heptan carbonyl) suberane methane amide (Im) and N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl)-suberane methane amide (In) With
By suberane formic acid and oxalyl chloride at CH 2Cl 230 minutes original places of middle reaction generate the suberane formyl chloride.Excessive oxalyl chloride is removed in decompression down.Then, repeat to prepare the method for Compound I e, except the suberane formyl chloride with equimolar amount replaces Benzoyl chloride, the reaction times is 3 days.Product carries out silica gel column chromatography, to contain the CH of 0.4% methyl alcohol 2Cl 2Make elutriant, at first obtain Compound I m (30%), it is yellow semi-solid thing.
1H NMR(CDCl 3)δ7.90(s，1H)，7.74(d，1H)，7.42(d，1H)，7.41(s，1H)，7.01(s，1H)，4.08(t，2H)，2.75(t，3H)，2.48(q，4H)，2.23(m，2H)，1.1-2.0(m，36H)，0.91(t，6H).
Calculated value: C 36H 45ClF 3N 3O 4676.3129.
Experimental value: 676.3115
Continue with the CH that contains 1-4% methyl alcohol 2Cl 2Carry out wash-out, must contain second component of In compound, productive rate is 43.9%, and it is a white solid, mp120-125 ℃.℃
1H NMR (CDCl 3) δ 8.40 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.59 (d, 1H), 7.47 (s, 1H), 7.30 (d, 2H), 4.08 (t, 2H), 2.75 (t, 2H), 2.47 (q, 4H), 2.41 (m, 1H), 1.4-2.1 (m, 12H), 0.93 (t, 6H). calculated value: C 28H 33ClF 3N 3O 3552.2241. experimental value: 552.22413. embodiment 12N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) diuresis acid amides (Io)
Figure C9210940000391
By with the chloroformic solution (Arnolds reagent) of 0.5N methylene dichloride-methyl chloride imonium (2ml is made by the chloroformic solution reaction of oxalyl chloride and DMF) reaction, will be in 5mlCH 2Cl 2In Uregit (303mg, 1mmol) activation 30 minutes.To wherein add the Ia amine compound (250mg, 0.585mmol) and triethylamine (153mg 115mmol), stirs mixture 14 hours, and reactant is at NaHCO 3The aqueous solution and CH 2Cl 2In distribute, organic layer washes with water, drying, concentrating under reduced pressure.Residue carries out chromatography with ready silica gel thin sheet, to contain the CH of 20% methyl alcohol 2Cl 2Make moving phase, get 250mg (69.8%) title compound, it is a yellow solid, m.p.173-175 ℃.
1H NMR(CDCl 3)δ8.46(s，1H)，7.80(s，1H)，7.62(d，1H)，7.50(s，1H)，7.40(d，1H)，7.10(d，2H)，6.85(d，1H)，5.90(s，1H)，5.55(s，1H)，4.70(s，2H)，4.07(m，2H)，2.85(m，1H)，2.60(m，3H)，2.40(t，2H)，1.10(t，3H)，1.0(t，6H).
Calculated value: C 33H 32ClF 3N 3O 3712.1360.
Experimental value: 712.1346.
Embodiment 13N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) cyclopentane formamide (Ip)
Figure C9210940000411
Repeat to prepare the method for Compound I o, except the cyclopentane-carboxylic acid with equimolar amount replaces Uregit.The productive rate of title compound is 58.3%, and it is a yellow oil.
1H NMR(CDCl 3)δ8.45(s，1H)，7.81(d，2H)，7.7(d，1H)，7.50(d，1H)，7.42(q，1H)，4.15(t，2H)，2.80(m，4H)，2.55(q，5H)，1.85(m，5H)，1.65(m，1H)，0.95(t，6H)；
Calculated value: C 26H 30N 3O 3F 3Cl 524.1928.
Experimental value: 524.1922.
Embodiment 144-acetaminosalicylic acid (IXa)
In 30 minutes to be in the 4-aminosallcylic acid that stirs and refluxing (76.57g, 0.5mmol) in the suspension of 250ml dehydrated alcohol, drip diacetyl oxide (83.2g, 0.815mmol).After finishing, mixture continues to reflux 15 minutes, then cooling.Filter collection product, with the small amount of ethanol washing, behind the air drying, 72.3g (74.15%) title compound, it is a gray solid, mp242-4 ℃, forefathers' report value mp is 234-5 ℃ (people such as p.Barraclongh, Eur.J.Chem.25, P.467,1990).
Embodiment 154-acetaminosalicylic acid allyl ester (Xa)
To be in stir sodium hydride down (4.0g, concentration 60%, 0.1mmol) in the suspension of 25ml DMF, dropping 4-acetaminosalicylic acid (19.5g, 50ml DMF solution 0.1mmol).Treat that the hydrogen effusion finishes, (12.1g 0.1mmol), stirs mixture 8.6 hours to wherein adding allyl bromide 98.DMF is removed in decompression, and residue carries out crystallization with methanol, gets 14.76g (62.76%) title compound, and it is a white solid, m.p.156-8 ℃.
1H-(CDCl 3)δ7.80(d，1H)，7.42(s，1H)，7.16(s，1H)，7.07(d，1H)，5.95-6.08(m，1H)，5.29-5.44(m.2H)4.80-4.83(m，2H)，2.19(s，3H).
MS (m/e) 236 is corresponding to M+H +
Embodiment 16N-(4-(allyloxycarbonyl)-3-(2-nitro-4-4-trifluoromethylphenopendant)) phenylacetamide (XIIa)
To be in stir sodium hydride down (1.69g, 60%, in 16ml DMF suspension 42mmol), adding 4-acetaminosalicylic acid allyl ester (10.0g, 42mmol).After treating that the hydrogen effusion finishes, (9.46g, 42mmol), mixture is in the heating down 45 minutes that refluxes to wherein adding 4-chloro-3-nitro-trifluoromethyl toluene.DMF is removed in decompression, and residue is made elutriant through purification by silica gel column chromatography with the methylene dichloride that contains 3% methyl alcohol, gets 13.0g (72.95%) title compound, and it is a white solid, m.p.160-163 ℃.
1H-NMR (CDCl 3) δ 8.22 (s, 1H), 8.03 (d, 1H), 7.68 (s, 1H), 7.61-7.65 (m, 3H), 7.3 6 (d, 1H), 6.83 (d, 1H), 5.65-5.78 (m, 1H), 5.10-5.21 (m, 2H), (m, 2H), 2.18 (s, 3H) .MS (m/e) 385 is corresponding to M+H for 4.57-4.60 +
Embodiment 17N-(4-(hydroxycarbonyl group)-3-(2-nitro-4-trifluoromethyl-phenoxy group)) phenyl-acetamides (XIIIa)
To three (dibenzalacetones), two palladiums (O) (550mg) and in the mixture formed of triphenylphosphine (660mg), add anhydrous methylene chloride (20ml), mixture stirred after 30 minutes, to wherein adding N-(4-(allyloxycarbonyl)-3-(2-nitro-4-trifluoromethyl-phenoxy group)) phenylacetamide (20.0g, 200mlCH 47mmol) 2Cl 2Solution, and then (9.61g, 57mmol) this sylvite is dissolved in 50ml ethyl acetate and CH to add the sylvite of 2 ethyl hexanoic acid 2Cl 2The solution of (3: 1) mixture.After 16 hours, with 75ml 1NHCl acidifying, divide water-yielding stratum with the mixture stirring, organic layer washes with water, drying, concentrating under reduced pressure, residue ether levigation gets 14.91g (82.6%) title compound, it is a white solid, uses the ether recrystallization, gets a sample, and its fusing point is 196-200 ℃.
1H-NMR(CDCl 3)δ8.06(s，1H)，7.86(d，1H)，7.61(s，1H)，7.49(d，1H)，7.36(d，1H)，6.75(d，1H)，2.01(s，3H).
MS (m/e) 385 is corresponding to M+H +
Embodiment 184-acetylaminohydroxyphenylarsonic acid N-(2-(diethylin) ethyl)-2-(2-nitro-4-4-trifluoromethylphenopendant) benzamide (XIVa)
To cold CH 2Cl 2Adding oxalyl chloride (20ml) (432mg, 3.4mmol), then in stirring down to wherein dripping DMF (0.3ml) in 5mlCH 2Cl 2Solution.Behind the restir 15 minutes, (1.153g 3mmol), stirs mixture 30 minutes to wherein adding N-(4-(hydroxycarbonyl group)-3-(2-nitro-4-4-trifluoromethylphenopendant)) phenyl-acetamides.To wherein adding N again, the N-diethyl ethylenediamine (415mg, 3.57mmol) and triethylamine (460mg, 4.55mmol) with mixture in stirring at room 1.5 hours, use NaHCO 3Solution washing, drying, concentrating under reduced pressure gets title compound, and it is an orange solids.
1H-NMR(CDCl 3)δ8.11(s，1H)，7.87(d，1H)，7.82(d，1H)，7.63(s，1H)，7.03(s，1H)，6.72(d，1H)，6.64(d，1H)，2.60-2.80(m，2H)，2.35-2.55(m，6H)，2.08(s，3H)，0.89(t，6H).
MS (m/e) 483 is corresponding to M+H. +
Embodiment 19 biological assay cell cultures:
The HCT116/VM46 cell is selected from human colon's cancer HCT116 clone, be used for research to the VM26 resistance, the MCF-7/ADR cell is selected from human breast cancer MCF-7 cell system, be used for resistance research to Zorubicin, two kinds of cell types all show the MDR phenotype, and the high level of MDR-1m RNA is had overexpression.Cell lies in the tissue culture flasks that contains McCoyShi 5A substratum and 10% foetal calf serum grows.Cell is stored under 37 ℃, and is containing 5%CO 2Wet air in, it is foster to carry out in per 5 days time being commissioned to train.Cell toxicant is measured:
Cell is planted in the droplet degree plate in 96 holes, and every hole has 5 * 10 3Individual cell, and make it to grow 24 hours down in 37 ℃.Use the antineoplastic agent culturing cell of the amount of falling progressively then, Zorubicin (100uM, peak concentration) or dactinomycin (17.6ng/ml), they correspond respectively to MCF-7 and HCT-116 cell.Add chemical sensitizer, the change in concentration scope is 0.08uM to 40uM.Abreast, adopt the isoptin of same concentrations to make positive control.Cultivate after 48 hours, washed cell, fixing, and use violet staining.By the droplet degree plate reader of molecular device (Molecular Devices), under the 595nM wavelength, read its optical density.IC 50Value (suppress 50% cell growth desired concn) can be measured by the relative survival rate that two to three times independent experiment draws.Term " times resistance " (fold resislance) is defined as: be with or without in the presence of the chemical sensitizer IC of antitumor drug in the resistant cell 50Value is present in the IC of antitumor drug in its responsive homologue 50Value is divided by, and the ratio that obtains promptly is.This value provides a kind of appraisal way to every kind of reversal agent in the apparent intensity aspect the raising efficacy of drugs.
Table I and Table II have provided representational chemical sensitizer among several the present invention, it be present in human colon's tumour HCT-116 resistant cell in and isoptin in the human breast cancer MCF-7 resistant cell compare, demonstrate higher MDR respectively and reverse active.
Table I
Chemical sensitizer is at human colon's cancer HCT-116
MDR reverse effect in the cell
Clone Compound (0.24 μ M) ActD IC 50 (ng/ml) Times resistance
HCT116 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 -- -- In Ik Im Ih Ip 0.5 8.9 1.2 1.2 1.4 1.4 1.7 1.0 15.6 2.4 2.4 2.8 2.8 3.4
HCT116 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 HCT-116/VM46 (0.4 μ M)----Id If Ij Ii Io Ig Ie Ib isoptin 0.5 1.0 1.2 1.6 1.6 1.7 1.8 2.0 2.5 3.0 5.8 1.0 20.0 2.4 3.2 3.2 3.4 3.6 4.0 5.0 6.0 11.6
The MDR reverse effect of Table II chemical stabilizer in human breast cancer MCF-Z cell
Clone Compound (0.24 μ M) ADR IC 50 (μM) Times resistance
MCF-7 MCF-7/ADR MCF-7/ADR MCF-7/ADR MCF-7/ADR -- -- In Ik Im 0.36 50 ＜2 3.7 4.8 1 138.9 ＜5.6 10.3 13.3
MCF-7/ADR MCF-7/ADR MCF-7/ADR MCF-7/ADR MCF-7/ADR MCF-7/ADR MCF-7/ADR (0.67 μ M) Ij Ih Ii If Ig Id isoptin 7.0 10.0 10.4 11.4 14.3 23 23 19.4 27.8 28.9 31.7 39.7 63.9 63.9
It is useful to the reverse of the MDR of cancer therapy drug that above-mentioned experiment has disclosed The compounds of this invention.Therefore, the invention still further relates to the purposes of tool compound of Formula I as a kind of adjuvant chemotherapy agent, it is of value to the resistance of change tumour to multiple medicine.
The tool compound of Formula I can form the acceptable acid salt of medicine.Described salt should be those negatively charged ion wherein not can to salt cause big toxicity and can with pharmaceutical carrier 5 usefulness of routine, adopt the salt of oral or parenteral route administration.The acceptable acid salt of medicine comprises the salt that tool compound of Formula I and ore deposit acid form, example hydrochloric acid, bromine hydracid, phosphoric acid, sulfuric acid; Also comprise the salt that forms with organic carboxyl acid or organic sulfonic acid, as acetate, citric acid, toxilic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix, oxysuccinic acid, methylsulfonic acid, isethionic acid, tosic acid and other known acid that is used for herbal medicine pharmaceutics aspect.Therefore, the invention further relates to the acceptable salt of medicine of tool compound of Formula I.
The mode of relevant whole body administration, dosage and dosage regimen must be at each individualities, utilize good occupational judgment and at the age of considering the experimenter, regulated in earnest under the factors such as body weight and physical appearance.Usually, when oral administration, the dosage of every day is about 0.1g-10g, is preferably 0.5-5g.In some cases, than can obtaining enough results of treatment under the low dosage, but under the other situation, then need heavy dose of.For the people who is familiar with clinical pharmacology, be conspicuous to following problem, promptly determining that containing compound of Formula I dosage every day is with single administration, or during the gradation administration, should be skilled in technique the worker understood thoroughly, and be those essential principles are taken into account in engineering practice to him.
Terminology used here " whole body administration " is meant the oral cavity, the hypogloeeis, and in the cheek, nasal cavity, skin, rectum, intramuscular, intravenously and route of administration such as subcutaneous.Usually can find, during the The compounds of this invention oral route,, give heavy dose of slightly active ingredient and could produce same effect than when the parenteral route.According to reliable clinical practice, The compounds of this invention administration concentration level preferably is that it can produce effectively, and useful effect does not cause any deleterious or undesirable side effects simultaneously again.
From treating, what give the patient usually is the formula of medicine that comprises compound of Formula I or acceptable acid salt of its medicine and medicine acceptable carrier, and the amount of the active ingredient in the prescription should make MDR reverse effectively.For making formula of medicine effective to this treatment, formula of medicine will contain a large amount of or in a small amount (for example, 95%-0.5%) at least a The compounds of this invention and pharmaceutical carrier, carrier comprises one or more solids, semisolid or liquid diluent, weighting agent and nontoxic, inert, and can be used as medical prescription auxiliary.This class formula of medicine should adopt dosage unit form, promptly on the physics solely from unit, it has the mark that is equivalent to dosage or multiple, the medication amount that is predetermined, this drug dose is to calculate by producing desired result of treatment.In usually using, dose unit contains 1,1/2, and 1/3 or single dose still less.Single dose preferably contains the amount that can effectively produce required result of treatment, this is to obtain according to the mode of taking that predetermined dosage regimen is once used one or more dose units, be generally dosage every day (gave once on the 1st, twice, three times or repeatedly) whole, half, 1/3rd or be less than it.Can envision, other therapeutical agent also can exist in such prescription.The formula of medicine that per unit dosage contains the 0.1-1g active ingredient is preferably, and can be prepared into tablet easily, lozenge, capsule, pulvis, water-based or oily suspensions, syrup, elixir and the aqueous solution.Oral dosage form is tablet and capsule preferably, and it can contain conventional vehicle, as tackiness agent (syrup for example, gum arabic, gelatin, Sorbitol Powder, tragacanth gum or polyvinylpyrrolidone), weighting agent is (for example, lactose, sucrose, W-Gum, calcium phosphate, Sorbitol Powder or glycine), lubricant is (for example, Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide), disintegrating agent (for example, starch) and wetting agent (for example, sodium lauryl sulphate).Solution or suspension that tool compound of Formula I and conventional medicine carrier are formed are used as non-intestinal drug delivery agent, as are used for the intravenous aqueous solution, or are used for the oily suspensions of intramuscular injection.Such composition has and is used for the required transparency of parenterai administration, stability and adaptability, it can press method preparation: active compound that will about 0.1%-10% (weight ratio) is dissolved in water or by multi-hydroxy fat alcohol such as glycerine, propylene glycol is in the vehicle that polyoxyethylene glycol or its mixture are formed.Polyethylene glycols is by nonvolatile, is generally liquid, and is soluble in water and organic liquid, and the mixture that molecular weight is about the polyethylene glycols of 200-1500 is formed.

Claims (15)

1. preparation has the method for the compound and the acceptable salt of medicine thereof of general formula I,
Figure C9210940000021
Wherein
P is 1-3;
R 1And R 2Represent hydrogen or carboxyl groups R respectively independently 6CO-,
R wherein 6Be C 1-6Alkyl, C 3～7Cycloalkyl, G 2-7Alkenyl, unsubstituted or be selected from halogen atom, C by 1-3 1-6Alkyl, C 1-6Alkoxyl group and C 1-6The phenyl that the substituting group of alkylthio replaces, or have the group of following general formula,
Figure C9210940000022
R 3Be hydrogen or chlorine; R 4And R 5Represent C respectively independently 1-6Alkyl; Comprising: (a) make compound with general formula VI React with compound with general formula VII, Wherein M is a positively charged ion, and Y is a halogen atom, and with the tool general formula I ' compound separate If desired, with formula I ' compound radicals R 6The CO-acidylate; Perhaps (b) will have a general formula X V compound 80-160 ℃ of heating down, and will have general formula I " compound separation
Figure C9210940000041
2. according to the method for claim 1, prepare the compound of general formula I, wherein P is 1, and R 6CO-is selected from following groups
Figure C9210940000042
C 1-6Alkyl CO-,
Figure C9210940000043
Wherein n is 1-5.
3. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl)-dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) benzamide.
4. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) crotonamide.
5. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (6, f) (1,4) oxygen azepine _-the 3-yl) propionic acid amide.
6. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) cyclopropane carboxamide.
7. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl)-the 2-methyl propanamide.
8. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) the tetramethylene methane amide.
9. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) cyclohexane carboxamide.
10. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl)-N-(ring carbonyl in heptan) suberane methane amide.
11. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) the suberane methane amide.
12. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) the diuresis acid amides.
13. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) cyclopentane formamide.
14. according to the method for claim 2, preparation N-(2-chloro-10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen azepine _-the 3-yl) ethanamide.
15. according to the method for claim 2, preparation N-(10,11-dihydro-10-(2-(diethylin) ethyl)-11-oxo-7-(trifluoromethyl) dibenzo (b, f) (1,4) oxygen chlorine is assorted _-the 3-yl) ethanamide.
CN92109400A 1991-08-26 1992-08-14 Dibenz [b,f] [1,4] oxazepin-11(10H)-ones for multidrug resistance reversing agents Expired - Fee Related CN1038749C (en)

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